2-(Thi)oxo-3-imidazolyl-(2)-tetrahydroimidazoles

ABSTRACT

Imidazoles of the formula I ##STR1## wherein one of the radicals R 1  and R 2  denotes hydrogen or lower alkyl and the other denotes the nitro group, R 3  is lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkyl-sulphonyl-lower alkyl or amino-lower alkyl, R 4  is oxo or thioxo, R 5  - if R 1  is the nitro group - is hydrogen, lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, amino-lower alkyl, acyl, aryl or a heterocyclic radical or R 5  -- if R 2  is the nitro group -- is aryl or a heterocyclic radical, with the exception of an optionally substituted 2-imidazolyl group, and alk is lower alkylene and their therapeutically usable salts, S-oxides, sulphones or N-oxides are useful as agents against amoebae, schistosomes, filariae, trichomonades and bacteria and as intermediates.

The invention relates to new imidazoles of the formula I ##STR2##wherein one of the radicals R₁ and R₂ denotes hydrogen or lower alkyland the other denotes the nitro group, R₃ is lower alkyl, hydroxy-loweralkyl, lower alkoxy-lower alkyl, lower alkylsulphonyl-lower alkyl oramino-lower alkyl, R₄ is oxo or thioxo, R₅ -- if R₁ is the nitro group-- is hydrogen, lower alkyl, hydroxy-lower alkyl, lower alkoxy-loweralkyl, amino-lower alkyl, acyl, aryl or a heterocyclic radical or R₅ --if R₂ is the nitro group -- is aryl or a heterocyclic radical, with theexception of an optionally substituted 2-imidazolyl group, and alk islower alkylene, as well as processes for their manufacture.

In the preceding and following text, lower radicals are above allradicals which contain up to 7 C atoms, especially up to 4 C atoms.

Examples of lower alkyl radicals are methyl, ethyl, n-propyl orisopropyl or straight-chain or branched butyl, pentyl, hexyl or heptyl,which can be bonded in any desired position.

Hydroxy-lower alkyl groups are above all those with at most 7 C atoms,preferably with at most 4 C atoms, in which the lower alkyl part has theabove meaning, such as, for example, hydroxymethyl, 3-hydroxy-n-propyland especially 2-hydroxyethyl.

Examples of lower alkoxy-lower alkyl radicals are those which possess upto 7 C atoms, preferably up to 4 C atoms, in each of the lower alkylparts, for example methoxymethyl, ethoxymethyl, n-propoxymethyl,n-butoxymethyl, 2-(n-butoxy)-ethyl, 3-(n-propoxy)-propyl or especially2-methoxyethyl.

Lower alkylsulphonyl-lower alkyl is, for example, a lower alkylmentioned above which carries a lower alkylsulphonyl group, with thelower alkyl part having the above meanings, such asmethylsulphonylmethyl, ethylsulphonylmethyl, 2-methylsulphonylethyl,n-propylsulphonylmethyl, 2-n-propylsulphonylethyl,3-n-propylsulphonyl-n-propyl or ethylsulphonylethyl, especially2-ethylsulphonylethyl.

Amino-lower alkyl is, for example, a lower alkyl mentioned above whichcarries an amino group, especially a tertiary amino group. A tertiaryamino group is, for example, di-lower alkylamino, such as dimethylamino,N-methyl-N-ethylamino, diethylamino, di-n-propylamino ordi-n-butylamino, or lower alkyleneamino wherein the lower alkylene partcan also be interrupted by hetero-atoms, such as oxa-loweralkyleneamino, thia-lower alkyleneamino or aza-lower alkylene amino, forexample pyrrolidino, piperidino, morpholino, thiomorpholino,2,6-dimethyl-thiomorpholino, piperazino, N'-methylpiperazino orN'-(β-hydroxy-ethyl)-piperazino. Accordingly, amino-lower alkyl is, forexample, dimethylaminomethyl, diethylaminomethyl, 2-dimethylaminomethyl,pyrrolidinomethyl, 2-pyrrolidino-ethyl, 3-pyrrolidino-n-propyl,piperidino-methyl, morpholino-methyl, 2-morpholino-ethyl,2-thiomorpholino-ethyl, piperazino-methyl, 2-piperazino-ethyl,N'-methyl-piperazinomethyl, 3-(N'-methylpiperazino)-n-propyl andN'-(β-hydroxyethyl)-piperazino-methyl.

Acyl is, for example, alkanoyl, especially lower alkanoyl, such aspropionyl, butyryl or especially acetyl or formyl, and also optionallysubstituted benzoyl, for example benzoyl substituted as indicated belowfor the aryl radicals.

Aryl R₅ is an optionally substituted aryl radical, for example amonosubstituted, disubstituted or polysubstituted phenyl or naphthylradical or an unsubstituted phenyl or naphthyl radical and also, forexample, an optionally substituted 5,6,7,8-tetrahydro-1- or -2-naphthylradical. An optionally monosubstituted or disubstituted phenyl ornaphthyl radical is preferred, an optionally monosubstituted phenylradical or naphthyl radical being preferred in particular, and anoptionally monosubstituted phenyl radical being preferred veryparticularly.

An aryl radical R₅ is, for example, substituted by the lower alkylgroups defined above.

An aryl radical R₅ can, however, also be substituted by a lower alkoxygroup defined above.

The aryl radical R₅ can also be substituted by halogen atoms or by thetrifluoromethyl group.

Possible halogen atoms are in particular chlorine atoms or bromineatoms, but especially fluorine.

A heterocyclic radical is, in particular, a heterocyclic radical ofaromatic or aliphatic character. Heterocyclic radicals are bonded via anatom which is a member of a heterocyclic ring.

A heterocyclic radical R₅ of aromatic character is, for example, amononuclear or polynuclear radical of aromatic character which containsat least one heterocyclic ring of aromatic character, possessing atleast one hetero-atom, as a constituent. Examples of suitablehetero-atoms are oxygen, sulphur and/or nitrogen atoms.

Suitable radicals of this nature are, for example, radicals possessingat least one five-membered ring which contain at least one hetero-atom,especially one of those mentioned above, such as furyl, benzo[b]furyl,thienyl, benzo[b]thienyl, pyrrolyl, indolyl, oxazolyl, thiazolyl,isooxazolyl, isothiazolyl, pyrazolyl, 3H-pyrazolyl, indazolyl,imidazolyl, furazanyl and triazolyl, such as, for example, 1H- or2H-1,2,4-triazolyl, radicals, thiadiazolyl radicals and tetrazolylradicals, as well as radicals possessing at least one six-membered ringwhich contain at least one hetero-atom, especially one of thosementioned above, such as pyridyl, quinolyl, isoquinolyl, acridinyl,pyrazinyl, pyrimidinyl, pyridazinyl, quinoxalinyl, phenazinyl,1,3,5-triazinyl and 1,2,4-triazinyl radicals.

The heterocyclic radicals of aromatic character can be monosubstituted,disubstituted or polysubsubstituted, but are preferably unsubstituted.

Possible substituents on carbon atoms of the heterocyclic radicals ofaromatic character which have been mentioned are in particular loweralkoxy groups, such as methoxy, ethoxy, propoxy and butoxy groups,trifluoromethyl groups, optionally substituted amino groups, nitrogroups, and especially hydroxyl groups, halogen atoms, such as fluorine,chlorine and bromine atoms, and above all lower alkyl radicals, such asmethyl, ethyl, propyl and isopropyl radicals, straight and branchedbutyl, pentyl and hexyl radicals bonded in any desired position, andphenyl radicals which are optionally substituted by lower alkyl, loweralkoxy, halogen or trifluoromethyl groups, and mercapto groups.

Optionally substituted amino groups are, for example, mono- or di-loweralkylamino groups, as well as acylamino groups and N-acyl-N-loweralkylamino groups, such as methylamino, ethylamino, dimethylamino,diethylamino, lower alkanoylamino, for example acetylamino, N-loweralkanoyl-N-lower alkylamino, for example N-acetyl-N-methylamino,benzoylamino and N-benzoyl-N-methylamino groups.

In heterocyclic radicals which carry a hydrogen atom on a ring nitrogenatom, the hydrogen atom can also be replaced by lower alkyl radicals oracyl radicals, especially benzoyl radicals which are optionallysubstituted, for example as indicated below for the aryl radicals, andabove all lower alkanoyl radicals, for example propionyl, butyryl andespecially acetyl radicals.

In heterocyclic radicals, oxidisable hetero-atoms can also be present inthe form of their oxides. Thus it is in particular possible for sulphuratoms to be S-oxidised or S-dioxidised and, above all, for nitrogenatoms to be N-oxidised.

The free valency of the heterocyclic radicals of aromatic character inparticular starts from a C atom belonging to the aromatic system.

A heterocyclic radical R₅ of aliphatic character is, for example, amonocyclic or polycyclic radical of aliphatic character which contains,as a constituent, at least one heterocyclic ring of aliphatic characterpossessing at least one hetero-atom, such as one of those mentionedabove.

Suitable radicals of this nature are, for example, radicals possessingat least one five-membered ring which contain at least one hetero-atom,especially one of those mentioned above, such as tetrahydrofuryl,tetrahydrothienyl, pyrrolidinyl, indolinyl, pyrazolinyl, pyrazolidinyl,4,5-alkylenethiazolyl-(2), 4,5-dihydro-thiazolyl, tetrahydrothiazolyl,imidazolinyl and imidazolidinyl radicals, as well as radicals possessingat least one six-membered ring which contain at least one hetero-atom,especially one of those mentioned above, such as pyranyl, for example2H- and 4H-pyranyl, tetrahydropyranyl, thiopyranyl, for example 2H- and4H-thiopyranyl, tetrahydrothiopyranyl, tetrahydropyridyl, for example1,2,3,4-tetrahydropyridyl, piperidyl, 1,2,3,4-tetrahydroquinolyl,oxazinyl, such as 2H-1,2-, 4H-1,2-, 6H-1,2-, 2H-1,3-, 4H-1,3-, and4H-1,4-oxazinyl, morpholinyl, thiazinyl, for example 2H-1,3-thiazinyl,thiomorpholinyl and piperazinyl radicals.

The heterocyclic radicals of aliphatic character can be monosubstituted,disubstituted or polysubstituted, but are preferably unsubstituted.

Possible substituents at carbon atoms of the heterocyclic radicals ofaliphatic character which have been mentioned are in particular alkoxyradicals, halogen atoms, hydroxyl groups and optionally substitutedamino groups, such as those mentioned above, and above all lower alkylradicals, such as those mentioned above.

Ring nitrogen atoms carring hydrogen atoms can be substituted, inparticular as indicated above, and oxidisable hetero-atoms can be in theform of their oxides, especially as indicated above.

The free valency of the heterocyclic radicals of aliphatic character inparticular starts from a C atom belonging to the heterocyclic structure.

Lower alkylene is branched or, in particular, straight-chain loweralkylene, for example with 2-4 C atoms in the alkylene chain, such as1,2-propylene, 1,2-butylene, 1,2-pentylene, 1,2-hexylene,2-methyl-1,2-propylene, 2,3-butylene, 1,3-butylene, 1,3-propylene,1,4-butylene or especially 1,2-ethylene.

The new compounds possess valuable pharmacological properties. Inparticular, they display effects against bacteria, especiallyGram-negative germs, protozoa and worms, such as trichomonodes,schistosomes, coccidiae, filariae and above all amoebae, as can be shownin animal experiments, for example on the liver of healthy hamsterswhich is artificially infected with Entamoeba histolytica, on oraladministration of about 30 to about 100 mg/kg. The new imidazolestherefore in particular are useful as agents against amoebae,schistosomes, filariae, trichomonades and bacteria. Furthermore, the newimidazoles can serve as starting products or intermediate products forthe manufacture of other compounds, especially therapeutically activecompounds.

Compounds preferred in particular are those of the formula Ia ##STR3##wherein R₂ is hydrogen or lower alkyl, R₃ is lower alkyl, hydroxy-loweralkyl, lower alkoxy-lower alkyl, lower alkylsulphonyl-lower alkyl oramino-lower alkyl, R₄ is oxo or thioxo and R₅ is hydrogen, lower alkyl,hydroxy-lower alkyl, lower alkoxy-lower alkyl, amino-lower alkyl, analkanoyl group, an optionally monosubstituted, disubstituted orpolysubstituted phenyl or naphthyl radical, an optionally substitutedfuryl, benzo[b]furyl, thienyl, benzo[b]thienyl, pyrrolyl, indolyl,oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, 3H-pyrazolyl,indazolyl, imidazolyl-(4), imidazolyl-(5), imidazolyl-(2), furazanyl,triazolyl, thiadiazolyl, pyridyl, quinolyl, isoquinolyl, acridinyl,pyrazinyl, pyrimidinyl, pyridazinyl, quinoxalinyl, phenazinyl, 1,3,5- or1,2,4-triazinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl,indolinyl, pyrazolinyl, pyrazolidinyl, 4,5-dihydro-thiazolyl,tetrahydro-thiazolyl, imidazolinyl, imidazolidinyl, pyranyl,tetrahydropyranyl, thiopyranyl, tetrahydrothiopyranyl,tetrahydropyridyl, piperidyl, 1,2,3,4-tetrahydroquinolyl, oxazinyl,morpholinyl, thiazinyl, thiomorpholinyl or piperazinyl radical or anoptionally C-lower alkylated pyrrolidino, piperidino, morpholino,thiomorpholino, piperazino, N'-lower alkyl-piperazino,N'-β-hydroxyethyl-piperazino or pyridinium radical and alk is loweralkylene, and their S-oxides, sulphones or N-oxides.

Imidazoles to be singled out much more are those of the formula Ib##STR4## wherein R₁ is hydrogen or lower alkyl, R₃ is lower alkyl,hydroxy-lower alkyl, lower alkoxy-lower alkyl, loweralkylsulphonyl-lower alkyl or amino-lower alkyl, R₄ is oxo or thioxo andR₅ is an optionally monosubstituted, disubstituted or polysubstitutedphenyl or naphthyl radical, an optionally substituted furyl,benzo[b]furyl, thienyl, benzo[b]thienyl, pyrrolyl, indolyl, oxazolyl,thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, 3H-pyrazolyl, indazolyl,imidazolyl-(4), imidazolyl-(5), furazanyl, triazolyl, thiadiazolyl,pyridyl, quinolyl, isoquinolyl, acridinyl, pyrazinyl, pyrimidinyl,pyridazinyl, quinoxalinyl, phenazinyl, 1,3,5- or 1,2,4-triazinyl,tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, indolinyl,pyrazolinyl, pyrazolidinyl, 4,5-dihydro-thiazolyl, tetrahydro-thiazolyl,imidazolinyl, imidazolidinyl, pyranyl, tetrahydropyranyl, thiopyranyl,tetrahydro-thiopyranyl, tetrahydropyridyl, piperidyl,1,2,3,4-tetrahydroquinolyl, oxazinyl, morpholinyl, thiazinyl,thiomorpholinyl or piperazinyl radical, or an optionally C-loweralkylated pyrrolidino, piperidino, morpholino, thiomorpholino,piperazino, N'-lower alkyl-piperazino, N'-β-hydroxyethyl-piperazino orpyridinium radical and alk is lower alkylene, and their S-oxides,sulphones or N-oxides.

Compounds to be singled out particularly are compounds Ic of the formulaIa, wherein R₂ is hydrogen or lower alkyl, R₃ is lower alkyl,hydroxy-lower alkyl, lower alkoxy-lower alkyl, loweralkylsulphonyl-lower alkyl, di-lower alkylaminolower alkyl, loweralkyleneamino-lower alkyl, lower oxaalkyleneamino-lower alkyl, or lowerthiaalkyleneamino-lower alkyl, R₄ is oxo or thioxo and R₅ is hydrogen,lower alkyl, hydroxylower alkyl, lower alkoxy-lower alkyl, di-loweralkylaminolower alkyl, lower alkyleneamino-lower alkyl, loweroxaalkyleneamino-lower alkyl, lower thiaalkyleneamino-lower alkyl, lowerazaalkyleneamino-lower alkyl, lower alkanoyl, an optionallymonosubstituted, disubstituted or polysubstituted phenyl radical, anoptionally substituted furyl, thienyl, pyrrolyl, indolyl, oxazolyl,thiazolyl, thiadiazolyl, 4,5-dihydrothiazolyl-(2),tetrahydro-thiazolyl-(2), pyrazolyl, indazolyl, imidazolyl-(5),imidazolyl-(4), imidazolyl-(2), pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, 1,3,5- or 1,2,4-triazinyl, pyrrolidinyl, pyrazolinyl,indolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidyl,morpholinyl, thiazinyl, thiomorpholinyl or piperazinyl radical, anoptionally C-lower alkylated pyrrolidino, piperidino, morpholino,thiomorpholino, piperazino, N'-lower alkyl-piperazino,N'-β-hydroxyethyl-piperazino or pyridinium radical and alk is1,2-ethylene, as well as their S-oxides, sulphones or N-oxides.

Further compounds to be singled out are imidazoles Id of the formula Ib,wherein R₁ is hydrogen or lower alkyl, R₃ is lower alkyl, hydroxy-loweralkyl, lower alkoxy-lower alkyl, lower alkylsulphonyl-lower alkyl,di-lower alkylaminolower alkyl, lower alkyleneamino-lower alkyl, loweroxaalkyleneamino-lower alkyl, lower thiaalkyleneamino-lower alkyl, orlower azaalkyleneamino-lower alkyl, R₄ is oxo or thioxo, and R₅ is anoptionally monosubstituted, disubstituted or polysubstituted phenylradical, an optionally substituted furyl, thienyl, pyrrolyl, indolyl,oxazolyl, thiazolyl, thiadiazolyl, 4,5-dihydro-thiazolyl-(2),tetrahydro-thiazolyl-(2), pyrazolyl, indazolyl, imidazolyl-(5),imidazolyl-(4), pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,3,5- or1,2,4-triazinyl, pyrrolidinyl, pyrazolinyl, indolinyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, piperidyl, morpholinyl, thiazinyl,thiomorpholinyl or piperazinyl radical, an optionally C-lower alkylatedpyrrolidino, piperidino, morpholino, thiomorpholino, piperazino,N'-lower alkyl-piperazino, N'-β-hydroxyethylpiperazino or pyridiniumradical and alk is 1,2-ethylene, as well as their S-oxides, sulphones orN-oxides.

Further compounds to be singled out are compounds Ie or the formula Ia,wherein R₂ is hydrogen or lower alkyl, R₃ is hydroxy-lower alkyl orlower alkyl, R₄ is oxo or thioxo and R₅ is hydrogen, lower alkyl,hydroxy-lower alkyl, lower alkoxylower alkyl, lower alkanoyl, anoptionally monosubstituted phenyl radical or an optionally substitutedthiazolyl, imidazolyl-(5), 4,5-dihydro-thiazolyl-(2),tetrahydrothiazolyl-(2), imidazolyl-(4), imidazolyl-(2), pyridyl,thiadiazolyl, morpholinyl, thiomorpholinyl, pyrimidinyl or piperazinylradical, an optionally C-lower alkylated pyrrolidino, piperidino,morpholino, thiomorpholino, piperazino, N'-lower alkyl-piperazino,N'-β-hydroxyethyl-piperazino or pyridinium radical and alk is1,2-ethylene, as well as their S-oxides, sulphones or N-oxides.

Compounds also to be singled out are compounds If of the formula Ib,wherein R₁ is hydrogen or lower alkyl, R₃ is hydroxy-lower alkyl orlower alkyl, R₄ is oxo or thioxo and R₅ is an optionally monosubstitutedphenyl radical or an optionally substituted thiazolyl, imidazolyl-(5),4,5-dihydrothiazolyl-(2), tetrahydro-thiazolyl-(2), imidazolyl-(4),pyridyl, thiadiazolyl, morpholinyl, thiomorpholinyl, pyrimidinyl orpiperazinyl radical, an optionally C-lower alkylated pyrrolidino,piperidino, morpholino, thiomorpholino, piperazino, N'-loweralkyl-piperazino, N'-β-hydroxyethyl-piperazino or pyridinium radical andalk is ethylene, as well as their S-oxides, sulphones or N-oxides.

Compounds to be particularly singled out are compounds Ig of the formulaIa, wherein R₂ is hydrogen or lower alkyl, R₃ is hydroxy-lower alkyl orlower alkyl, R₄ is oxo or thioxo and R₅ is hydrogen, lower alkyl,hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkanoyl, anoptionally o-, m- or p-halogenated phenyl radical or an optionallysubstituted thiazolyl, 4,5-dihydro-thiazolyl-(2),tetrahydro-thiazolyl-(2), imidazolyl-(5), imidazolyl-(4),imidazolyl-(2), thiadiazolyl, pyridyl, or morpholinyl radical, anoptionally lower alkylated thiomorpholinyl radical, optionally loweralkylated pyrimidinyl radical or optionally lower alkylated piperazinylradical, an optionally C-lower alkylated pyrrolidino, piperidino,morpholino, thiomorpholino, N-piperazino, N'-lower alkylpiperazino,N'-β-hydroxyethyl-piperazino or pyridinium radical and alk is ethylene,as well as their S-oxides, sulphones or N-oxides.

Compounds which are equally suitable are compounds Ih of the formula Ib,wherein R₁ is hydrogen or lower alkyl, R₃ is hydroxy-lower alkyl orlower alkyl, R₄ is oxo or thioxo and R₅ is an optionally o-, m- orp-halogenated phenyl radical, or an optionally substituted thiazolyl,4,5-dihydro-thiazolyl-(2), tetrahydro-thiazolyl-(2), imidazolyl-(5),imidazolyl-(4), thiadiazolyl, pyridyl, morpholinyl, optionally loweralkylated thiomorpholinyl, optionally lower alkylated pyrimidinyl oroptionally lower alkylated piperazinyl radical, an optionally C-loweralkylated pyrrolidino, piperidino, morpholino, thiomorpholino,piperazino, N'-lower alkyl-piperazino, N'-β-hydroxyethyl-piperazino orpyridinium radical and alk is ethylene, as well as their S-oxides,sulphones or N-oxides.

Suitable compounds are above all those of the formula Ia wherein R₂ ishydrogen or lower alkyl, R₃ is hydroxy-lower alkyl or lower alkyl, R₄ isoxo or thioxo and R₅ is hydrogen, lower alkyl, hydroxy-lower alkyl,lower alkoxy-lower alkyl, propionyl, butyryl, acetyl, formyl, phenyl,o-, m- or p-fluorophenyl, 4-thiazolyl, 2-thiazolyl,4,5-dimethyl-thiazolyl-(2), cyclopentano-[1,2-d]-thiazolyl-(2),5-amino-1,3,4-thiadiazolyl-(2), 4,5-dihydro-thiazolyl-(2),tetrahydrothiazolyl-(2), 4-acetyl-thiazolyl-(2), 5-acetyl-thiazolyl-(2),5-methylsulphonyl-thiazolyl-(2), pyridyl-(2), pyridyl-(3), pyridyl-(4),4,6-dimethyl-pyridyl-(2), 3,5-dimethyl-pyridyl(2), pyrimidinyl-(2),pyrimidinyl-(5), 2,6-dihydroxypyrimidinyl-(4),2,4-dimethyl-pyrimidinyl-(5), 4,6-dimethylpyrimidinyl-(2),pyrrolidinyl-(2), piperidyl-(3), imidazolyl-(2), imidazolyl-(4),imidazolyl-(5), thiadiazolyl-(2), 5-methyl-thiadiazolyl-(2),5-ethyl-thiadiazolyl-(2), or an optionally C-lower alkylated pryidiniumradical and alk is ethylene.

Compounds which are very much more suitable are those of the formula Ibwherein R₁ is hydrogen or lower alkyl, R₃ is hydroxy-lower alkyl orlower alkyl, R₄ is oxo or thioxo and R₅ is phenyl, o-, m- orp-fluorophenyl, 4-thiazolyl, 2-thiazolyl, 4,5-dimethyl-thiazolyl-(2),cyclopentano-[1,2-d]-thiazolyl-(2), 5-amino-1,3,4-thiadiazolyl-(2),4,5-dihydrothiazolyl-(2), tetrahydro-thiazolyl-(2),4-acetyl-thiazolyl-(2), 5-acetyl-thiazolyl-(2),5-methylsulphonyl-thiazolyl-(2), pyridyl-(2), pyridyl-(3), pyridyl-(4),4,6-dimethyl-pyridyl-(2), 3,5-dimethyl-pyridyl-(2), pyrimidinyl-(2),pyrimidinyl-(5), 2,6-dihydroxy-pyrimidinyl-(4),2,4-dimethyl-pyrimidinyl-(5), 4,6-dimethyl-pyrimidinyl-(2),pyrrolidinyl-(2), piperidyl-(3), piperidyl-(1), imidazolyl-(4),imidazolyl-(5), thiadiazolyl-(2), 5-methyl-thiadiazolyl-(2),5-ethyl-thiadiazolyl-(2) or an optionally C-lower alkylated pyridiniumradical and alk is ethylene.

Particularly suitable compounds are those of the formula Ia, wherein R₂is hydrogen or methyl, R₃ is 2-hydroxyethyl or methyl, R₄ is oxo, R₅ ishydrogen, methyl, hydroxymethyl, propionyl, acetyl, formyl, phenyl,p-fluorophenyl, thiazolyl-(2), cyclopentano-[1,2-d]-thiazolyl-(2),5-acetyl-thiazolyl-(2), 5-methylsulphonyl-thiazolyl-(2), pyridyl-(2),pyrimidinyl-(2), thiadiazolyl-(2) or 5-ethylthiadiazolyl-(2) and alk isethylene.

Even more suitable compounds are those of the formula Ib wherein R₁ ishydrogen or methyl, R₃ is 2-hydroxyethyl or methyl, R₄ is oxo, R₅ isphenyl, p-fluorophenyl, thiazolyl-(2),cyclopentanol[1,2-d]-thiazolyl-(2), 5-acetyl-thiazolyl-(2),5-methylsulphonyl-thiazolyl-(2), pyridyl-(2), pyrimidinyl-(2),piperidyl-(3), thiadiazolyl-(2) or 5-ethyl-thiadiazolyl-(2) and alk isethylene.

Amongst these new imidazoles of the formula I there should in particularbe mentioned1,3-di-[1-methyl-5-nitroimidazolyl-(2)]-2-oxo-tetrahydroimidazole,1[thiazolyl-(2)]-2-oxo-3-[1-methyl-4-nitro-imidazolyl-(2)]-tetrahydroimidazole,1-[5-methylsulphonyl-thiazolyl-(2)[-2-oxo-3-[1-methyl-5-nitro-imidazolyl-(2)-tetrahydroimidazole,1-[pyrimidinyl-(2)]-2-oxo-3-[1-methyl-5-nitro-imidazolyl-(2)[-tetrahydroimidazole,1-[1,3,4-thiadiazolyl-(2)[-2-oxo-3-[1-methyl-5-nitroimidazolyl-(2)[-tetrahydroimidazole,[cyclopentano-[1,2-d]-thiazolyl-(2)]-2-oxo-3-[1-methyl-5-nitro-imidazolyl-(2)]-tetrahydroimidazoleand especially1[thiazolyl-(2)]-2-oxo-3-[1-methyl-5-nitroimidazolyl-(2)]-tetrahydroimidazole.

The new imidazoles are obtained according to methods which are inthemselves known.

Thus, for example, the new imidazoles can be manufactured by reacting animidazole of the formula II ##STR5## wherein R₁, R₂ and R₃ have theabove meaning and X is a reactive esterified hydroxyl group, a reactiveetherified hydroxyl group, a free or etherified mercapto group, anammonium group or especially a sulphonyl group, with a compound of theformula III ##STR6## wherein R₄, R₅ and alk have the above meaning.

A reactive esterified hydroxyl group X is, in particular, a hydroxylgroup esterified by a strong inorganic or organic acid, above all ahydrogen halide acid, such as hydrochloric acid, hydrobromic acid orhydriodic acid, also sulphuric acid or an organic sulphonic acid, suchas an aromatic sulphonic acid, for example benzenesulphonic acid,p-bromobenzenesulphonic acid or p-toluenesulphonic acid, or an aliphaticsulphonic acid, such as an alkanesulphonic acid, for examplemethanesulphonic acid or ethanesulphonic acid. Thus, X in particularrepresents chlorine, bromine or iodine.

A reactive etherified hydroxyl group is, for example, a hydroxyl groupetherified with an aromatic or aliphatic alcohol, above all a loweraliphatic alcohol, such as an optionally substituted phenoxy group or analkoxy group, above all a lower alkoxy group, and especially methoxy orethoxy.

An etherified mercapto group is, for example, an optionally substitutedphenylmercapto or benzylmercapto group or, in particular, a loweralkylmercapto group, such as the ethylmercapto or methylmercapto group.

An ammonium group is, in particular, a quaternary ammonium group, aboveall a tri-lower alkylammonium group, for example the trimethylammoniumgroup or triethylammonium group, or the cation of an aromatic nitrogenbase, for example the pyridinium or quinolinium group.

A sulphonyl group is, in particular, a sulphonyl group derived from anorganic sulphonic acid, especially from an aromatic sulphonic acid.Thus, x in particular represents benzenesulphonyl,p-bromobenzenesulphonyl, p-toluenesulphonyl or methylsulphonyl.

This reaction can be carried out in the usual manner. It is preferablycarried out in the presence of a basic condensation agent, oralternatively the compound of the formula III is employed in the form ofits N-metal derivative, such as its N-alkali metal derivative, which isobtainable, for example, from the compound of the formula III and anamide, hydride, hydrocarbon compound, hydroxide or alcoholate of analkali metal, such as lithium, sodium or potassium, and which can beused without isolation. Suitable basic condensation agents are, forexample, alkali metal hydroxides or alkaline earth metal hydroxides,such as sodium hydroxide, potassium hydroxide and calcium hydroxide, ororganic tertiary nitrogen bases, such as trialkylamines, for exampletrimethylamine and triethylamine, or pyridine. It is furthermore alsopossible to employ an excess of the compound of the formula III,especially if R₅ in a compound of the formula III is not hydrogen. Thereaction is advantageously carried out at elevated temperature and/or inthe presence of an inert solvent, such as a solvent possessing polarfunctional groups, for example dimethylformamide, dimethylacetamide,dimethylsulphoxide, acetonitrile or cyclic aliphatic ethers, such asdioxane and tetrahydrofurane.

In resulting compounds, substituents can be introduced, modified orsplit off within the scope of the definition of the end products.

Thus it is possible, in resulting compounds in which R₃ is hydroxy-loweralkyl, to convert R₃ in the usual manner into a lower alkoxy-lower alkylradical. Thus it is possible, for example, to react a resultinghydroxy-lower alkyl compound with a reactive ester, for example one ofthose mentioned above, of a lower alkanol, preferably in the presence ofa basic condensation agent, such as one of those mentioned, for examplean alkali metal hydroxide, or with a diazo-lower alkane, such asdiazomethane, preferably in the presence of boron trifluoride.

In resulting compounds in which R₄ is thioxo, R₄ can be converted intothe oxo group in the usual manner, especially according to methods ofhydrolysis which are in themselves known, for example by treating theresulting thioxo compounds with an alkaline agent, such as an alkalimetal hydroxide, in the presence of an oxidising agent, such as hydrogenperoxide.

In resulting compounds in which R₅ is hydrogen, a radical R₅ whichdiffers from hydrogen can be introduced in the usual manner. Theintroduction can in particular be achieved by reacting the resultingcompounds of the formula I with a compound R₅ X, wherein R₅ has theabove meaning but differs from hydrogen and X is a reactively esterifiedhydroxyl group, such as one of those mentioned, especially a halogenatom, for example a chlorine atom, or a benzenesulphonyl group. Di-loweralkyl sulphate, such as dimethylsulphate, is in particular also suitablefor the alkylation reaction. If a 1-hydroxy-lower alkyl radical, forexample the hydroxymethyl radical, R₅ is to be introduced, the resultingcompound of the formula I can also be reacted with an oxo-lower alkyl,for example with formaldehyde in order to introduce hydroxymethyl. If a2-hydroxy-lower alkyl radical, for example the 2-hydroxyethyl radical,R₅ is to be introduced, the resulting compound can also be reacted witha 1,2-epoxy-lower alkyl, for example with ethylene oxide in order tointroduce 2-hydroxyethyl. The reaction is preferably carried out in aneutral or weakly acid medium.

Thus it is possible, for example, to react resulting compounds of theformula VII ##STR7## wherein R₁, R₂, R₃, R₄ and alk have the abovemeaning, with a compound of the formula X-R₅, wherein R₅ has the abovemeaning and X is a reactive esterified hydroxyl group, a reactiveetherified hydroxyl group, a free or etherified mercapto group, anammonium group or a sulphonyl group.

A reactive esterified hydroxyl group, a reactive etherified hydroxylgroup, a free or etherified mercapto group, an ammonium group and asulphonyl group are groups such as have been described above.

The reaction can be carried out in the usual manner. It is preferablycarried out under the same conditions as have been described for thereaction of compounds of the formula II with compounds of the formulaIII.

Resulting compounds in which R₅ is hydrogen can be acylated in the usualmanner, especially by reaction with an acylating agent. Possibleacylating agents are carboxylic acids, preferably in the form of theirfunctional derivatives, such as halides, especially chlorides, oranhydrides, for example pure or mixed anhydrides, or internalanhydrides, such as ketenes, or esters, such as esters with loweralkanols, such as methanol or ethanol, or cyanomethyl esters.

In resulting compounds in which R₅ is acyl, it is possible to replace R₅by hydrogen in the usual manner. Thus it is possible to hydrolyse anacylamino compound, preferably catalysed by acids, for example byhydrochloric acid or sulphuric acid.

In resulting compounds in which R₅ is hydroxy-lower alkyl, R₅ can beconverted into a lower alkoxy-lower alkyl radical in the usual manner,for example as described for the conversion of R₃. However, it is alsopossible to convert a hydroxy-lower alkyl radical R₅ into an amino-loweralkyl radical in the usual manner. Thus it is possible first to converta resulting hydroxy-lower alkyl compound into a compound possessing areactively esterified hydroxy-lower alkyl radical, a reactive esterbeing, in particular, an ester of strong inorganic or organic acids,such as, in particular, hydrogen halide acids, for example hydrochloricacid, hydrobromic acid or hydriodic acid, toluenesulphonic acids, suchas, in particular, arylsulphonic acids, for example benzenesulphonicacid or toluenesulphonic acids, alkylsulphonic acids or sulphuric acid.For example, a hydroxy-lower alkyl compound can be converted into ahalogeno-lower alkyl compound by treatment with halogenating agents,such as thionyl chloride, phosphorus oxychloride or phosphoruspentabromide. In the resulting reactive ester the reactively esterifiedhydroxyl group can then be replaced in the usual manner by an aminogroup, for example by treatment with corresponding amines.

In compounds of the general formula I which possess an amino-lower alkylgroup with at least one hydrogen atom bonded to a nitrogen atom as R₃,the hydrogen atom can be substituted in the usual manner. Thus it is inparticular possible to follow the procedure of reacting a compound ofthe formula I, in which R₃ is a primary or secondary amino group, with areactive ester of an alcohol corresponding to a substituent of the aminogroup of the amino-lower alkyl radical.

Furthermore it is possible to N-oxidise an imidazole of the formula Iwhich carries a N-heterocyclic radical as the radical R₅.

The oxidation is carried out in the usual manner, for example withN-oxidising agents, such as hydrogen peroxide, ozone, inorganicper-acids, for example persulphuric acids, such as caro's acid, orespecially organic peroxy compounds, above all organic per-acids, suchas peracetic acid, pertrifluoroacetic acid, perbenzoic acid ormonoperphthalic acid, which can also be substituted, for example byhalogen atoms, such as chlorine atoms, for instancechloromonoperphthalic acid or m-chloroperbenzoic acid or tertiaryhydroperoxide compounds, such as tert.-butyl peroxide or cumeneperoxide, optionally in the presence of catalysts such as vanadium,titanium or molybdenum compounds.

Resulting compounds of the formula I, in which R₅ is a N-oxidisedN-heterocyclic radical, can be converted by reduction into thecorresponding compounds of the formula I, in which R₅ is aN-heterocyclic radical.

The reduction is carried out in the usual manner, advantageously by theaction of phosphorus halides.

Resulting compounds of the formula I, in which the aliphatic radical R₅is a S-unsubstituted heterocyclic radical, can be oxidised to theS-oxides (sulphoxides) or S-dioxides (sulphones).

The oxidation to the sulphoxides or sulphones can be carried out in amanner which is in itself known, for example by reaction with aS-oxidising agent, such as hydrogen peroxide, per-acids, especiallyperacetic acid, perbenzoic acids or monoperphthalic acids, which canalso be substituted, for example by halogen atoms,1-chlorobenzotriazole, chromic acid, potassium permanganate, hypohalitesor nitric acid, nitrous gases and the like, or electrolytically. Inthese reactions, the sulphoxides are obtained at lower temperatures,especially if good cooling is used, or if only one mol equivalent of theoxidising agent is used, whilst on warming and/or using at least 2 molequivalents of the oxidising agent the sulphones are obtained. Theoxidation to sulphoxides can in particular also be effected by reactionwith 2,4,4,6-tetrabromocyclohexadienone in a solvent containing anether, for example in dioxane/water or tetrahydrofurane, preferably inthe presence of sodium acetate.

Resulting S-oxides can be oxidised to the S-dioxides. This oxidation canbe effected in a manner which is in itself known, for example as in thecase of the oxidation described above which leads to the dioxides.

Resulting S-oxides can be reduced to the corresponding S-unsubstitutedcompounds of the formula I, for example with a reducing agent, such as adi-light metal hydride, for example with sodium borohydride, or a lightmetal hydride such as diborane or a borohydride-etherate, for exampleBH₃ -tetrahydrofurane, or above all dichloroborane or, for example, withacetyl chloride, sulphites or hydriodic acid, or especially withtriphenylphosphine.

In the above reductions care must be taken, where relevant, that furthergroups which can be reduced are not attacked. Thus care must inparticular be taken, during the reduction, that any halogen atoms bondedto aromatic rings which may be present are not replaced by hydrogen. Inaddition, a thioether grouping requires attention in the case of allreductions, especially catalytic hydrogenations. Very particularly, itis necessary to ensure that the nitro group (R₁ or R₂) is not reduced.Catalysts which are not affected by sulphur are preferentially to beused, and if necessary the hydrogen absorption should be followedvolumetrically and the hydrogenation stopped after the calculated amounthas been absorbed.

Compounds of the formula I which contain a radical R₅ which can benitrated (aryl, or a heterocyclic radical of aromatic character) can benitrated in a known manner and especially as described above.

Compounds of the formula I which contain a nitro group as the radical R₂can be rearranged to give the corresponding 4-nitroimidazoles, that isto say compounds of the formula I which contain a nitro group as theradical R₁. Such a rearrangement is effected, for example, by the actionof, for instance, an excess of alkali metal iodide, especially potassiumiodide, in the presence of an inert solvent, preferably a solvent withpolar functional groups, such as dimethylformamide, dimethylacetamide,dimethylsulphoxide, acetonitrile or hexamethylphosphoric acid triamide.

The rearrangement of R₂ =nitro compounds into R₁ =nitro compounds of theformula I can also be effected by the action of an iodide whichcorresponds to the radical R₃, namely R₃ I, such as, for example, theaction of methyl iodide on compounds of the formula I which contain amethyl group as the R₃ radical. In this rearrangement, the unsubstitutednitrogen atom of the imidazole ring is quaternised. Thereafter, thequaternary salt is pyrolised. This rearrangement also takes place, forexample, in the presence of an inert solvent, preferably the solventsdescribed above.

The subsequent conversions can be carried out individually or incombination and in any desired sequence. Care must be taken in theindividual operations that other functional groups are not attacked.

Depending on the process conditions and the starting substances, thefinal substances are obtained in the free form or in the form of theiracid addition salts which is also included in the invention. Thus, forexample, basic, neutral or mixed salts and where relevant alsohemihydrates, monohydrates, sesquihydrates or polyhydrates thereof canbe obtained. The acid addition salts of the new compounds can beconverted into the free compound in a manner which is in itself known,for example with basic agents, such as alkalis or ion exchangers. On theother hand, the resulting free bases can form salts with organic orinorganic acids. The acids used for the manufacture of acid additionsalts are in particular those suitable for forming therapeuticallyusable salts. As examples of such acids there may be mentioned: hydrogenhalide acids, sulphuric acids, phosphoric acids, nitric acid, perchloricacid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic acids orsulphonic acids, such as formic acid, acetic acid, propionic acid,succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid,citric acid, ascorbic acid, maleic acid, hydroxymaleic acid or pyruvicacid; phenylacetic acid, benzoic acid, or p-aminobenzoic acid,anthranilic acid, p-hydroxybenzoic acid, salicylic acid orp-aminosalicylic acid, embonic acid, methanesulphonic acid,ethanesulphonic acid, hydroxyethanesulphonic acid and ethylenesulphonicacid; halogenobenzenesulphonic acid, toluenesulphonic acid,naphthalenesulphonic acid or sulphanilic acid; methionine, tryptophane,lysine or arginine.

These or other salts of the new compounds, such as, for example, thepicrates, can also serve for the purification of the resulting freebases, by converting the free bases into salts, isolating these andagain liberating the bases from the salts. Because of the closerelationships between the new compounds in the free form and in the formof their salts, the free compounds are where appropriate also to beunderstood to include the corresponding salts, in the preceding andfollowing text.

The invention also relates to those embodiments of the process in whicha process is stopped at any stage or in which a compound obtainable asan intermediate product at any stage is used as the starting compoundand the missing steps are carried out, or a starting substance is formedunder the reaction conditions or used, where relevant, in the form of asalt and/or racemate or optical antipode.

Depending on the number of the asymmetrical C atoms and on the choice ofthe starting substances and procedures, the new compounds can be in theform of racemate mixtures, racemates or optical antipodes.

Racemate mixtures can be separated into the pure racemates on the basisof the physico-chemical differences of the constituents, in a knownmanner, for example by chromatography and/or fractional crystallisation.

Pure racemates can be resolved into the diastereomers according to knownmethods, for example by recrystallisation from an optically activesolvent, with the aid of microorganisms or by reaction with an opticallyactive acid which forms salts with the racemic compound and separationof the salts obtained in this manner, for example on the basis of theirdifferent solubilities, and from the diastereomers the antipodes can beliberated by the action of suitable agents. Particularly customaryoptically active acids are, for example, the D- and L-forms of tartaricacid, di-o-toluyltartaric acid, malic acid, mandelic acid,camphorsulphonic acid or quinic acid. Advantageously, the more active ofthe two antipodes is isolated.

According to the invention it is, however, also possible to obtain theend products in the form of the pure racemates or optical antipodes byemploying starting substances containing one or more asymmetrical Catoms in the form of the pure racemates or optical antipodes.

Appropriately, those starting substances which lead to the finalsubstances which have initially been particularly singled out areemployed for carrying out the reactions according to the invention.

The starting substances are known or can, if they are new, by obtainedaccording to methods which are in themselves known. New startingsubstances also form a subject of the invention.

The reactions mentioned are carried out in the usual manner in thepresence or absence of diluents, condensation agents and/or catalyticagents, at lowered, ordinary or raised temperature, optionally in aclosed vessel. If appropriate, the reaction is carried out at highdilution (dilution principle).

The new compounds can be used, for example, in the form ofpharmaceutical preparations in which they are present in the free formor optionally in the form of their salts, especially the therapeuticallyusable salts, mixed with a pharmaceutical, organic or inorganic, solidor liquid excipient which is suitable, for example, for enteral orparenteral administration. Possible substances which can form theexcipient are those which do not react with the new compounds such as,for example, water, gelatine, lactose, starch, stearyl alcohol,magnesium stearate, talc, vegetable oils, benzyl alcohols, gum,propylene glycols, white petroleum jelly or other known medicinalexcipients. The pharmaceutical preparations can, for example, be in theform of tablets, dragees, capsules or suppositories or in a liquid formas solutions (for example as an elixir or syrup), suspensions oremulsions. They are optionally sterilised and/or contain auxiliaries,such as preservatives, stabilisers, wetting agents or emulsifiers,solubilising agents or salts for regulating the osmotic pressure orbuffers. They can also contain other therapeutically valuablesubstances. The pharmaceutical preparations are formulated according tocustomary methods. The dosage of the new compounds can vary depending onthe compound and on the individual requirements of the patient.Preferably, a daily dose of about 0.25 to 1.0 g is administered to awarm-blooded organism weighing about 70 kg.

The new compounds can also be used in veterinary medicine, for examplein one of the abovementioned forms or in the form of feedstuffs or ofadditives to animal fodder. For this, for example, the customaryextenders and diluents or feedstuffs are used.

The invention is described in more detail in the examples which follow.

EXAMPLE 1

A solution of 8.5 g of 1-[thiazolyl-(2)]-2-oxo-tetrahydroimidazole in200 ml of dimethylformamide is added dropwise over the course of 1 hourto a suspension of 2.4 g of 50% strength sodium hydride in 50 ml ofdimethylformamide at 20° C to 30° C, whilst stirring. Thereafter, themixture is stirred for a further hour at 20° C to 30° C. 10.3 g of1-methyl-2-methylsulphonyl-5-nitro-imidazole, dissolved in 75 ml ofdimethylformamide, are then added and the whole is stirred for a furtherhour at 90° C to 100° C. Thereafter the reaction mixture is evaporatedand the evaporation residue is washed with petroleum ether, trituratedwith approx. 50 ml of water, filtered off and first washed thoroughlywith water and then with methanol. The crude product is recrystallisedfrom 100 ml of 2-ethoxyethanol. The 1-[thiazolyl-(2)]-2-oxo-3-[1-methyl-5-nitro-imidazolyl-(2)]-tetrahydroimidazole thus obtained, ofthe formula ##STR8## melts at 226° C.

EXAMPLE 2

10 g of1,3-di-[1-methyl-5-nitro-imidazolyl-(2)]-2-oxo-tetrahydroimidazole(melting point 211° C-212° C), 25 g of potassium iodide and 125 ml ofdimethylformamide are heated for 20 hours under reflux. The reactionmixture is then evaporated to dryness and the evaporation residue istriturated with water and filtered off. The crude product is firstrecrystallised from 35 ml of dimethylformamide and then againrecrystallised from 50 ml of dimethylformamide.1,3-Di-[1-methyl-4-nitro-imidazolyl-(2)]-2-oxo-tetrahydroimidazole thusobtained, of the formula ##STR9## melts at 263° C-265° C.

EXAMPLE 3

A solution of 5.3 g of 1-[5-acetyl-thiazolyl-(2)]-2-oxo-tetrahydroimidazole in 100 ml of dimethylformamide is addeddropwise over the course of 30 minutes to a suspension of 1.2 g of 50%strength sodium hydride in 40 ml of dimethylformamide at 20°-30° C,whilst stirring. Thereafter the mixture is stirred for a further 2 hoursat 20°-30° C. 5.2 g of 1-methyl-2-methylsulphonyl-5-nitro-imidazoledissolved in 50 ml of dimethylformamide are then added and the mixtureis stirred for a further hour at 90°-100° C. The reaction mixture isthen evaporated and the evaporation residue is washed with petroleumether, triturated with 100 ml of water, filtered off and firstthoroughly washed with water and then with isopropanol. The resultingcrude product is recrystallised from 15 ml of dimethylformamide.1-[5-Acetyl-thiazolyl-(2)]-2-oxo-3-[1-methyl-5-nitro-imidazolyl-(2)]-tetrahydroimidazolethus obtained, of the formula ##STR10## melts at 275°-277° C, withdecomposition.

1-[5-Acetyl-thiazolyl-(2)]-2-oxo-tetrahydroimidazole required as thestarting material, can be obtained, for example, by condensation of2-amino-5-acetyl-thiazole with β-chloroethylisocyanate and subsequentcyclisation (for example treatment with a base, such as sodium hydroxidesolution or sodium acetate). It melts at 271°-274° C, withdecomposition.

EXAMPLE 4

A solution of 9.0 g of 1-(4-fluorophenyl)-2-oxo-tetrahydroimidazole in75 ml of dimethylformamide is added dropwise over the course of 1 hourto a suspension of 2.4 g of 50% strength sodium hydride in 75 ml ofdimethylformamide at 20°-30° C, whilst stirring. Thereafter the mixtureis stirred for a further hour at 20°-30° C. 10.3 g of1-methyl-2-methylsulphonyl-5-nitro-imidazole, dissolved in 75 ml ofdimethylformamide, are then added and the whole is stirred for a furtherhour at 90°-100° C. The reaction mixture is then evaporated and theevaporation residue is triturated with 100 ml of water, filtered off andfirst thoroughly washed with water, then with isopropanol and finallyalso with petroleum ether. The crude product is recrystallised from 85ml of 2-ethoxy-ethanol.1-(4-Fluorophenyl)-2-oxo-3-[1-methyl-5-nitro-imidazolyl-(2)]-tetrahydroimidazole,thus obtained, of the formula ##STR11## melts at 216°-218° C.

1-(4-Fluorophenyl)-2-oxo-tetrahydroimidazole required as the startingmaterial, can be obtained, for example, by condensation of4-fluoroaniline with β-chloroethylisocyanate and subsequent cyclisation.It melts at 148°-149° C.

EXAMPLE 5

A solution of 8.2 g of 1-[pyrimidinyl-(2)]-2-oxo-tetrahydroimidazole in200 ml of dimethylformamide is added dropwise over the course of 40minutes to a suspension of 2.4 g of 50% strength sodium hydride in 75 mlof dimethylformamide at 40° to 50° C, whilst stirring. Thereafter themixture is stirred for a further 1 hour 30 minutes at 50° C. 10.3 g of1-methyl-2-methylsulphonyl-5-nitro-imidazole dissolved in 75 ml ofdimethylformamide are then added and the mixture is stirred for afurther hour at 90° to 100° C. After cooling, the reaction product whichhas precipitated is filtered off, introduced into 70 ml of water, againfiltered off and thoroughly washed with water, isopropanol and finallyalso with petroleum ether.1-[Pyrimidinyl-(2)]-2oxo-3-[1-methyl-5-nitro-imidazolyl-(2)]-tetrahydroimidazole,thus obtained, of the formula ##STR12## melts at 264°-266° C, withdecomposition.

1-[Pyrimidinyl-(2)]-2-oxo-tetrahydroimidazole required as the startingmaterial, can be obtained, for example, by condensation of2-amino-pyrimidine with β-chloroethylisocyanate and subsequentcyclisation. It melts at 235°-136° C.

EXAMPLE 6

A solution of 10.5 g of1-[cyclopentano[1,2-d]-thiazolyl-(2)]-2-oxo-tetrahydroimidazole in 200ml of dimethylformamide is added dropwise over the course of 1 hour to asuspension of 2.4 g of 50% strength sodium hydride in 75 ml ofdimethylformamide at 30° to 40° C, whilst stirring. Thereafter themixture is stirred for a further hour at 30° to 40° C. 10.3 g of1-methyl-2-methylsulphonyl-5-nitroimidazole dissolved in 75 ml ofdimethylformamide are then added and the whole is stirred for a furtherhour at 90° to 100° C. The reaction mixture is then evaporated and theevaporation residue is triturated with 100 ml of water, filtered off andfirst thoroughly washed with water, then with isopropanol and finallyalso with petroleum ether. The crude product is recrystallised from 130ml of 2-ethoxyethanol.1-[Cyclopentano[1,2-d]-thiazolyl-(2)]-2-oxo-3-[1methyl-5-nitroimidazolyl-(2)]-tetrahydroimidazole,thus obtained, of the formula ##STR13## melts at 221°-222° C.

1[Cyclopentano[1,2-d]-thiazolyl-(2)]-2-oxo-tetrahydroimidazole, requiredas the starting material, can be obtained, for example, by condensationof 2-amino-cyclopentano [1,2-d]-thiazole with β-chloroethylisocyanateand subsequent cyclisation. It melts at 257° C.

EXAMPLE 7

A solution of 8.2 g of 1-[pyridyl-(2)]-2-oxo-tetrahydroimidazole in 100ml of dimethylformamide is added dropwise over the course of 1 hour to asuspension of 2.4 g of 50% strength sodium hydride in 75 ml ofdimethylformamide at 40° to 50° C, whilst stirring. Thereafter themixture is stirred for a further hour at 40° to 50° C. 10.3 g of1-methyl-2-methylsulphonyl-5-nitro-imidazole dissolved in 75 ml ofdimethylformamide are then added and the whole is stirred for a furtherhour at 90° to 100° C. Thereafter the reaction mixture is evaporated andthe evaporation residue is triturated with 200 ml of water, filtered offand first washed thoroughly with water, then with isopropanol andfinally also with petroleum ether. The crude product, which melts at210°-213° C, is recrystallised from 50 ml of 2-ethoxyethanol.1-[Pyridyl-(2)]-2-oxo-3-[1-methyl-5-nitroimidazolyl-(2-]-tetrahydroimidazole, thus obtained,of the formula ##STR14## melts at 213°-215° C.

1-[Pyridyl-(2)]-2-oxo-tetrahydroimidazole used as the starting material,can be obtained, for example, by condensation of 2-aminopyridine withβ-chloroethylisocyanate and subsequent cyclisation. It melts at165°-166° C.

EXAMPLE 8

A solution of 8.1 g of1-[1,3,4-thiadiazolyl-(2)]2-oxo-tetrahydroimidazole in 150 ml ofdimethylformamide is added dropwise over the course of 1 hour to asuspension of 2.3 g of 50% strength sodium hydride in 75 ml ofdimethylformamide at 30° to 40° C, whilst stirring. Thereafter themixture is stirred for a further hour at 30° to 40° C. 9.8 g of1-methyl-2-methylsulphonyl-5-nitro-imidazole dissolved in 75 ml ofdimethylformamide are then added and the whole is stirred for a furtherhour at 90° to 100° C. Thereafter the reaction mixture is evaporated andthe evaporation residue is triturated with 100 ml of water, filtered offand first thoroughly washed with water, then with isopropanol andfinally also with petroleum ether. The crude product, which melts at188°-190° C, is recrystallised from 85 ml of 2-ethoxy-ethanol. 1-[1,3,4-thiadiazolyl-(2)]-2-oxo-3-[1-methyl-5-nitro-imidazolyl-(2)]-tetrahydroimidazole,thus obtained, of the formula ##STR15## melts at 192°-194° C.

1-[1,3,4-Thiadiazolyl-(2)]-2-oxo-tetrahydroimidazole, required as thestarting material, can be obtained, for example, by condensation of2-amino-1,3,4-thiadiazole with β-chloroethylisocyanate and subsequentcyclisation. It melts at 240°-241° C.

EXAMPLE 9

A solution of 5.6 g of1-[5-methylsulphonyl-thiazolyl-(2)]-2-oxo-tetrahydroimidazole in 75 mlof dimethylformamide is added dropwise over the course of 1 hour to asuspension of 1.1 g of 50% strength sodium hydride in 40 ml ofdimethylformamide at 30°-40° C, whilst stirring. Thereafter the mixtureis stirred for a further hour at 30°-40° C. 4.7 g of1-methyl-2-methylsulphonyl-5-nitro-imidazole dissolved in 50 ml ofdimethylformamide are then added and the whole is stirred for 1 hour at90°-100° C. Thereafter the reaction mixture is evaporated and worked upas described in Example 8. The crude product, which melts at 222°-228°C, is recrystallised from 200 ml of 2-ethoxy-ethanol.1-[5-Methylsulphonylthiazolyl-(2)]-2-oxo-3-[1-methyl-5-nitro-imidazolyl-(2)]-tetrahydroimidazole,thus obtained, of the formula ##STR16## melts at 230° C-232° C, withdecomposition.

1-[5-Methylsulphonyl-thiazolyl-(2)]-2-oxo-tetrahydroimidazole, requiredas the starting material, can be obtained, for example, by condensationof 2-amino-5-methylsulphonylthiazole with β-chloroethylisocyanate andsubsequent cyclisation. It melts at 246° C.

EXAMPLE 10

A solution of 10.7 g of1-[5-nitro-thiazolyl-(2)]-2-oxo-tetrahydroimidazole in 200 ml ofdimethylformamide is added dropwise over the course of 1 hour to asuspension of 2.4 g of 50% strength sodium hydride in 75 ml ofdimethylformamide at 20° C to 30° C, whilst stirring. Thereafter themixture is stirred for a further hour at 20° C to 30° C. 10.3 g of1-methyl-2-methylsulphonyl-5-nitro-imidazole, dissolved in 75 ml ofdimethylformamide, are then added and the whole is stirred for a furtherhour at 80° C to 90° C. The reaction mixture is then acidified withglacial acetic acid whilst cooling with ice and is evaporated, and theevaporation residue is dissolved in 300 ml of ethylene chloride andextracted by shaking 5 times with 100 ml of water at a time. Theethylene chloride extract is dried with anhydrous magnesium sulphate andevaporated and the evaporation residue is first recrystallised from 60ml of 2-ethoxy-ethanol and then again from 25 ml of 2-ethoxy-ethanol.1-[5-Nitro-thiazolyl-(2)]-2-oxo-3-[1-methyl-5-nitro-imidazolyl-(2)]-tetrahydroimidazole,thus obtained, of the formula ##STR17## melts at 197°-199° C.

EXAMPLE 11

Tablets containing 250 mg of active substance are manufactured in theusual manner, for example to have the following composition per tablet:

    ______________________________________                                        Composition                                                                   ______________________________________                                        1-[Thiazolyl-(2)]-2-oxo-3-[1-methyl-5-nitro-                                  imidazolyl-(2)]-tetrahydroimidazole                                                                       250 mg                                            Lactose                     36 mg                                             Wheat starch                100 mg                                            Colloidal silica            16 mg                                             Talc                        16 mg                                             Magnesium stearate          2 mg                                                                          420 mg                                            ______________________________________                                    

MANUFACTURE

1-[Thiazolyl-(2)]-2-oxo-3-[1-methyl-5-nitroimidazolyl-(2)]-tetrahydro-imidazoleis mixed with the lactose, a part of the wheat starch and with colloidalsilica and the mixture is forced through a sieve, whereby a powdermixture is obtained. A further part of the wheat starch is worked into apaste with a 5-fold amount of water on a water bath and the powdermixture is kneaded with this paste until a slightly plastic mass hasbeen produced.

The plastic mass is forced through a sieve of approx. 3 mm mesh widthand dried and the dry granules are again forced through a sieve.Thereafter the remaining wheat starch, talc and magnesium stearate aremixed in and the resulting mixture is pressed to give tablets weighing420 mg (having a breaking groove).

I claim:
 1. An imidazole compound of the formula ##STR18## wherein oneof the radicals R₁ and R₂ denotes hydrogen or lower alkyl and the otherdenotes a nitro group, R₃ is lower alkyl, hydroxy-lower alkyl, loweralkoxy-lower alkyl, R₄ is oxo, R₅ is pyrimidinyl-(2), and "alk" isethylene, and the N-oxides and a therapeutically acceptable acidaddition salt thereof.
 2. An imidazole compound as claimed in claim 1 ofthe formula Ia ##STR19## wherein R₂ is hydrogen or methyl, R₃ is2-hydroxyethyl or methyl, R₄ is oxo, R₅ is pyrimidinyl-(2), and alk isethylene and a therapeutically acceptable acid addition salt thereof. 3.An imidazole compound as claimed in claim 1 of the formula Ib ##STR20##wherein R₁ is hydrogen or methyl, R₃ is 2-hydroxyethyl or methyl, R₄ isoxo, R₅ is pyrimidinyl-(2), and alk is ethylene and a therapeuticallyacceptable acid addition salt thereof.
 4. A compound as claimed in claim1 being1-[pyrimidinyl-(2)]-2-oxo-3-[1-methyl-5-nitroimidazolyl-(2)]-tetrahydroimidazole.5. An antimicrobial pharmaceutical preparation comprising anantimicrobially effective amount of a compound claimed in claim 1,together with a pharmaceutically usable excipient.